Chemicals with elevated bioaccumulation profiles present potential hazards to public health and the environment. Ionizable organic compounds (IOCs) increasingly represent a large proportion of commercial chemicals; however, historical approaches for bioaccumulation determinations are mainly developed for neutral chemicals, which were not appropriate for IOCs. Herein, we employed the zebrafish embryo, a common vertebrate model in environmental and biomedical studies, to elucidate toxicokinetics and bioconcentration of eight IOCs with diverse physicochemical properties and pharmacokinetic parameters. At an environmentally relevant pH (7.5), most IOCs exhibited rapid uptake and depuration in zebrafish, suggesting the ionized forms of IOCs are readily bioavailable. Bioconcentration factors (BCF) of these IOCs ranged from 0.0530 to 250 L•kg −1 wet weight. The human pharmacokinetic proportionality factor, apparent volume of distribution (V D ), better predicted the BCF of selected IOCs than more commonly used hydrophobicity-based parameters (e.g., pH-dependent octanol−water distribution ratio, D ow ). Predictive bioaccumulation models for IOCs were constructed and validated using V D alone or with D ow . Significant relationships between fish BCF and human V D , which is readily available for pharmaceuticals, highlighted the utility of biologically based "read-across" approaches for predicting bioaccumulative potential of IOCs. Our novel findings thus provided an understanding of the partitioning behavior and improved predictive bioconcentration modeling for IOCs.
Big data approaches have greatly improved scientific decision making, but they are highly dependent on the availability of data, impeding their use in data-poor scenarios. In addition to data abundance, enhancing data diversity is likewise a way to access knowledge. Herein, we propose a data-driven method for toxicity endpoint selection when directly relevant data are deficient, and shale gas exploitation sites were used as an example scenario. From the 1173 substances in the U.S. Environmental Protection Agency’s HFList, the most concerning endpoints in zebrafish embryo toxicity tests (FET) were inferred using a newly developed relational database (RDB) strategy that integrated chemical, high-throughput screening (HTS) bioactivity, genome, and FET endpoint information. This RDB strategy based on text mining and data fusion approaches enabled the integration of 255 bioactive contaminants, 955 HTS bioassays with known modes of action (MoAs), 214 gene ontologies, 65 pathways, and 27 phenotypic data and predicted measurement endpoints within 10 MoAs for shale gas pollution. This data-driven approach was further validated using zebrafish FET and transcriptomic sequencing with field-collected samples and achieved 89% and 97% accuracy for the predictive ontologies and pathways, respectively. This highlighted the applicability of RDB-based data-driven strategies for predicting toxicity endpoints from a priori knowledge of contaminants by improving data diversity.
While zebrafish (Danio rerio) have been accepted worldwide for evaluating chemical hazards to aquatic vertebrates, and in some countries it is mandated to generate fish toxicity data using native species, such as Chinese rare minnow (Gobiocypris rarus) in China. This represents an additional regulatory constraint that may cause redundant tests, additional animal uses, and higher costs. Previous studies showed that juvenile G. rarus was more sensitive than zebrafish juveniles and embryos to metals. To better understand the sensitivity of G. rarus to organic chemicals, we selected 29 fragrance ingredients belonging to various chemical classes and with differing physicochemical properties, for which good quality zebrafish acute toxicity data were available and tested them with juvenile G. rarus and embryo D. rerio using the Organisation of Economic Co-operation and Development test guidelines. Chemical toxicity distribution (CTD) and chemical ratio distribution (CRD) models were established to systematically compare the sensitivity between juveniles of G. rarus and D. rerio, as well as between D. rerio embryos and juveniles. The results of the CTD models showed that for tested chemicals, the sensitivity of juvenile G. rarus was similar to that of D. rerio juveniles and embryos. The CRD comparisons revealed that juvenile G. rarus was slightly less sensitive by a factor of ~2 than juvenile D. rerio to ingredients belonging to Verhaar class 3 and Ecological Structure Activity Relationship ester class, while comparable to other chemicals. These comparative experiments demonstrated that fish toxicity data with G. rarus can be submitted for use in chemical registrations outside China, which would avoid repeating animal tests using D. rerio. Meanwhile, the similar sensitivity of zebrafish juveniles and embryos to fragrance ingredients confirmed the suitability of replacing juveniles by zebrafish embryos.
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